Selenium Dibromide Click Chemistry: The Efficient Synthesis of Novel Selenabicyclo[3.3.1]nonene-2 and -nonane Derivatives

Highly efficient and convenient methods for the preparation of 35 novel derivatives of 9-selenabicyclo[3.3.1]nonane and 9-selenabicyclo[3.3.1]nonene-2 in high yields based on the adduct of the transannular addition of SeBr2 to 1,5-cyclooctadiene were developed. The methods for the amination of the adduct made it possible to obtain both diamino selenabicyclo[3.3.1]nonane derivatives and their dihydrobromide salts in one step in 88–98% yields. The methods meet the criteria of click chemistry. Compounds with high glutathione peroxidase mimetic activity were found among water-soluble dihydrobromide salts. The selective reaction of 2,6-dibromo-9-selenabicyclo[3.3.1]nonane with acetonitrile to form 6-bromo-9-selenabicyclo[3.3.1]nonene-2 was discovered. The latter compound served as a promising starting material to give rise to the new class of selenabicyclo[3.3.1]nonene-2 derivatives, e.g., 6-alkoxy-9-selenabicyclo[3.3.1]nonenes were obtained in 94–99% yields.


Introduction
After the discovery of an essential biological role of selenium, the organic chemistry and biochemistry of this element began to develop rapidly.A number of organoselenium species were found in the human body, including selenoamino acids and seleniumcontaining enzymes, which were identified as important biocatalysts [1][2][3][4][5][6][7][8][9].
The presence of nitrogen-containing groups in organoselenium compounds is favorable for the manifestation of biological activity (Figure 1).Many Se/N heterocycles exhibit various kinds of biological activity .Some examples of functionalized organoselenium compounds with N-containing substituents, exhibiting biological activity, including GPx mimetic properties, are presented in Figure 1 [17][18][19][20][21]32].
A comprehensive review on the medicinal chemistry of adamantane derivatives demonstrated great potential of this class of compounds for the discovery of new drugs [46].The high lipophilicity of the adamantane derivatives ensures the easy penetration of the drug through the blood-brain barrier [45,46].In addition, due to this property, the amantadine derivatives can exhibit antispasmodic properties.The first adamantane derivative to be used as a medicine was amantadine (Figure 2).It was originally used as an antiviral drug effective against the influenza A2 virus.Its antiparkinsonian effect was later discovered [45,46].Memantine is an NMDA antagonist used in the treatment of Alzheimer's disease, but is also being tested in clinical trials as a possible therapy for a number of other conditions, including HIV-associated dementia and multiple sclerosis (Figure 2) [46].Rimantadine is a drug active against influenza viruses and it used for the treatment and prevention of influenza (Figure 2).Tromantadine is active against Herpes viruses (Figure 2).Other active adamantane derivatives that are active ingredients in drugs include dopamantine, vildagliptin and carmantadine [45,46].It has been established that adamantane analogues containing oxygen atoms in the tricyclic fragment of adamantane (oxaadamantanes) inhibit the replication of SARS-CoV-2 viruses [46].Examples of biologically active functionalized organoselenium compounds with nitrogencontaining groups: ebselen [38][39][40][41][42][43][44] and compounds with antibacterial [11], anti-HIV [16], and antiproliferative [11] activities, phosphodiesterase inhibitor [11], and GPx mimics [32].
A comprehensive review on the medicinal chemistry of adamantane derivatives demonstrated great potential of this class of compounds for the discovery of new drugs [46].The high lipophilicity of the adamantane derivatives ensures the easy penetration of the drug through the blood-brain barrier [45,46].In addition, due to this property, the amantadine derivatives can exhibit antispasmodic properties.The first adamantane derivative to be used as a medicine was amantadine (Figure 2).It was originally used as an antiviral drug effective against the influenza A2 virus.Its antiparkinsonian effect was later discovered [45,46].Memantine is an NMDA antagonist used in the treatment of Alzheimer's disease, but is also being tested in clinical trials as a possible therapy for a number of other conditions, including HIV-associated dementia and multiple sclerosis (Figure 2) [46].Rimantadine is a drug active against influenza viruses and it used for the treatment and prevention of influenza (Figure 2).Tromantadine is active against Herpes viruses (Figure 2).Other active adamantane derivatives that are active ingredients in drugs include dopamantine, vildagliptin and carmantadine [45,46].It has been established that adamantane analogues containing oxygen atoms in the tricyclic fragment of adamantane (oxaadamantanes) inhibit the replication of SARS-CoV-2 viruses [46].
One of the aims of this research is to synthesize new heterocyclic compounds, containing selenium atoms and amino groups in the form of hydrobromides, that can be structurally close to adamantane drugs (Figure 2).The presence of the selenium atom may impart a new beneficial effect to this lipophilic scaffold (e.g., GPx mimetic properties) along with possible antiviral activity.
number of other conditions, including HIV-associated dementia and multiple sclerosis (Figure 2) [46].Rimantadine is a drug active against influenza viruses and it used for the treatment and prevention of influenza (Figure 2).Tromantadine is active against Herpes viruses (Figure 2).Other active adamantane derivatives that are active ingredients in drugs include dopamantine, vildagliptin and carmantadine [45,46].It has been established that adamantane analogues containing oxygen atoms in the tricyclic fragment of adamantane (oxaadamantanes) inhibit the replication of SARS-CoV-2 viruses [46].We obtained the adduct of the transannular addition of selenium dichloride to 1,5cyclooctadiene, which was used in collaborative studies with researchers at the Scripps Research Institute to estimate the anchimeric assistance effect of the selenium atom compared with that of the sulfur atom [56].The rates of nucleophilic substitution reactions in 2,6-dichloro-9-thia-and 2,6-dichloro-9-selenabicyclo[3.3.1]nonanes were measured in these studies.It was found that the anchimeric assistance effect of the selenium atom is approximately two orders of magnitude greater than the effect of the anchimeric assistance of sulfur [56].
Sharpless, one of the founders of click chemistry [60], and coworkers used 2,6dichloro-9-thiabicyclo [3.3.1]nonane in several studies for the preparation of various 9thiabicyclo[3.3.1]nonanederivatives and considered this compound "a privileged, bivalent scaffold for the display of nucleophilic components" [61] and the click chemistry reagent, which provided the efficient and selective synthesis of the target products including compounds with biological activity [61][62][63].Inter alia, fragmentable oligocationic compounds, which can be used for drug delivery and gene delivery into the cells, were obtained based on these compounds [63].Selenium analogs, 2,6-dihalo-9-selenabicyclo[3.3.1]nonanes,show higher reactivity compared to 2,6-dichloro-9-thiabicyclo[3.3.1]nonane and can be also considered as the click chemistry reagents.
In connection with the coronavirus epidemic, safe vaccination and the reduction or elimination of undesirable post-vaccination reactions of the body are of particular importance.Compounds with high GPx mimetic activity can be used as metabolic correctors on the vaccination process, which reduce or eliminate the pathological reactions of the body including oxidative stress during the vaccination and post-vaccination period.
We recently synthesized 2,6-dipyridinium-9-selenabicyclo[3.3.1]nonanedibromide, which was found to be a prospective drug for metabolic correction in the vaccination and post-vaccination period [64].This is the result of the joint research with the Irkutsk Anti-Plague Research Institute of Siberia and the Far East.The introduction of this compound into the body of experimental animals significantly reduces the development of pathological reactions [64].It is worth noting that 2,6-dipyridinium-9-selenabicyclo[3.3.1]nonanedibromide and other selenabicyclo[3.3.1]nonanederivatives do not exhibit toxicity [64].Thus, it is relevant to search for new organoselenium compounds with high GPx mimetic activity, which can also be used as metabolic correctors in the vaccination process, in the series of selenabicyclo[3.3.1]nonanederivatives.

Results and Discussion
The aim of this research is to develop efficient syntheses of novel functionalized (especially diamino) derivatives of 9-selenabicyclo[3.3.1]nonane, which are promising candidates for the manifestation of GPx mimetic activity.The use of click chemistry principles is an important feature of this work.Prospective metabolic correctors of the vaccination process and possible antiviral agents (Figure 2) can be found among 9-selenabicyclo[3.3.1]nonanederivatives with high GPx activity.Like the adamantane framework, the structure of 9-selenabicyclo[3.3.1]nonane has high lipophilic properties, and diamino derivatives of 9-selenabicyclo[3.3.1]nonane can be considered structurally close to adamantane antiviral drugs (Figure 2) [45,46].Additionally, high GPx activity can import additional beneficial effects to these products.

Results and Discussion
The aim of this research is to develop efficient syntheses of novel functionalized (especially diamino) derivatives of 9-selenabicyclo[3.3.1]nonane, which are promising candidates for the manifestation of GPx mimetic activity.The use of click chemistry principles is an important feature of this work.Prospective metabolic correctors of the vaccination process and possible antiviral agents (Figure 2) can be found among 9-selenabicyclo[3.3.1]nonanederivatives with high GPx activity.Like the adamantane framework, the structure of 9-selenabicyclo[3.3.1]nonane has high lipophilic properties, and diamino derivatives of 9-selenabicyclo[3.3.1]nonane can be considered structurally close to adamantane antiviral drugs (Figure 2) [45,46].Additionally, high GPx activity can import additional beneficial effects to these products.
The reaction of diethylamine with compound 2 proceeded smoothly at room temperature in methylene chloride to give product 4 in 90% yield in the form of dihydrobromide (Scheme 2).The reaction of unsaturated diallylamine with compound 2 in methylene chloride was sluggish, but when the reaction was carried out in acetonitrile, product 5 was obtained in 93% yield (Scheme 2).Thus, diallylamine is less nucleophilic than diethylamine and reacts efficiently in acetonitrile, which is a more polar solvent compared to methylene chloride.Products 4 and 5 were formed as precipitates, which easily separated from the reaction mixture by filtration.
The morpholine, piperidine and pyrrolidine cycles are present in many drugs and can be considered the pharmacophore groups.Morpholine, piperidine and pyrrolidine To study the amination reaction of compound 2, various amines were chosen: diethylamine, diallylamine, morpholine, piperidine, pyrrolidine, allylamine, isopropylamine, diisopropylamine, butylamine, isobutylamine, tert-butylamine, benzylamine, phenylamine and 2-vinyloxyethylamine.We began our study of the amination with the reaction of compound 2 with secondary amines, which usually gives monoalkylated products.
The reaction of diethylamine with compound 2 proceeded smoothly at room temperature in methylene chloride to give product 4 in 90% yield in the form of dihydrobromide (Scheme 2).

Results and Discussion
The aim of this research is to develop efficient syntheses of novel functionalized (especially diamino) derivatives of 9-selenabicyclo[3.3.1]nonane, which are promising candidates for the manifestation of GPx mimetic activity.The use of click chemistry principles is an important feature of this work.Prospective metabolic correctors of the vaccination process and possible antiviral agents (Figure 2) can be found among 9-selenabicyclo[3.3.1]nonanederivatives with high GPx activity.Like the adamantane framework, the structure of 9-selenabicyclo[3.3.1]nonane has high lipophilic properties, and diamino derivatives of 9-selenabicyclo[3.3.1]nonane can be considered structurally close to adamantane antiviral drugs (Figure 2) [45,46].Additionally, high GPx activity can import additional beneficial effects to these products.
The reaction of diethylamine with compound 2 proceeded smoothly at room temperature in methylene chloride to give product 4 in 90% yield in the form of dihydrobromide (Scheme 2).The reaction of unsaturated diallylamine with compound 2 in methylene chloride was sluggish, but when the reaction was carried out in acetonitrile, product 5 was obtained in 93% yield (Scheme 2).Thus, diallylamine is less nucleophilic than diethylamine and reacts efficiently in acetonitrile, which is a more polar solvent compared to methylene chloride.Products 4 and 5 were formed as precipitates, which easily separated from the reaction mixture by filtration.
The morpholine, piperidine and pyrrolidine cycles are present in many drugs and can be considered the pharmacophore groups.Morpholine, piperidine and pyrrolidine The reaction of unsaturated diallylamine with compound 2 in methylene chloride was sluggish, but when the reaction was carried out in acetonitrile, product 5 was obtained in 93% yield (Scheme 2).Thus, diallylamine is less nucleophilic than diethylamine and reacts efficiently in acetonitrile, which is a more polar solvent compared to methylene chloride.Products 4 and 5 were formed as precipitates, which easily separated from the reaction mixture by filtration.
The morpholine, piperidine and pyrrolidine cycles are present in many drugs and can be considered the pharmacophore groups.Morpholine, piperidine and pyrrolidine were successfully involved in the nucleophilic substitution reaction with compound 2 to form corresponding dihydrobromide products 6-8 in 91-95% yields (Scheme 3).
were successfully involved in the nucleophilic substitution reaction with compound 2 to form corresponding dihydrobromide products 6-8 in 91-95% yields (Scheme 3).Primary amines usually react with two equivalents of alkyl halide and it is difficult to carry out the monoalkylation.However, we succeeded in the development of the alkylation of compound 2 with two equivalents of primary amines with the formation of products with secondary amine groups in the form of dihydrobromide.In this case, it was necessary to use more acetonitrile (compared to the reactions in Schemes 2 and 3) to prevent "crosslinking", i.e., the reaction of one molecule of primary amine with two molecules of compound 2. Various primary amines such as allylamine, isopropylamine, butylamine, isobutylamine, tert-butylamine, benzylamine and phenylamine were involved in the reaction with compound 2, affording corresponding diamino dihydrobromide derivatives 9-15 in high yields (Scheme 4).The main part of the primary amines gave the products 9-14 in 91-96% yields.In the case of tert-butylamine, the yield of the product 15 was slightly lower (88%).
The products in the form of dihydrobromide salts (Schemes 2-4) precipitated from the reaction mixture and can be easy isolated by filtration.It should be emphasized that these products did not require additional purification.The compounds obtained were generally white, beige, yellowish or slightly orange-tinted powders.
Compounds, containing vinyloxy groups, are valuable intermediates for organic synthesis, capable of electrophilic addition and polymerization.The amine functional-Scheme 3. The synthesis of the products 6-8 from cyclic amines and compound 2.
Primary amines usually react with two equivalents of alkyl halide and it is difficult to carry out the monoalkylation.However, we succeeded in the development of the alkylation of compound 2 with two equivalents of primary amines with the formation of products with secondary amine groups in the form of dihydrobromide.In this case, it was necessary to use more acetonitrile (compared to the reactions in Schemes 2 and 3) to prevent "crosslinking", i.e., the reaction of one molecule of primary amine with two molecules of compound 2. Various primary amines such as allylamine, isopropylamine, butylamine, isobutylamine, tert-butylamine, benzylamine and phenylamine were involved in the reaction with compound 2, affording corresponding diamino dihydrobromide derivatives 9-15 in high yields (Scheme 4).
were successfully involved in the nucleophilic substitution reaction with compound 2 to form corresponding dihydrobromide products 6-8 in 91-95% yields (Scheme 3).Primary amines usually react with two equivalents of alkyl halide and it is difficult to carry out the monoalkylation.However, we succeeded in the development of the alkylation of compound 2 with two equivalents of primary amines with the formation of products with secondary amine groups in the form of dihydrobromide.In this case, it was necessary to use more acetonitrile (compared to the reactions in Schemes 2 and 3) to prevent "crosslinking", i.e., the reaction of one molecule of primary amine with two molecules of compound 2. Various primary amines such as allylamine, isopropylamine, butylamine, isobutylamine, tert-butylamine, benzylamine and phenylamine were involved in the reaction with compound 2, affording corresponding diamino dihydrobromide derivatives 9-15 in high yields (Scheme 4).The main part of the primary amines gave the products 9-14 in 91-96% yields.In the case of tert-butylamine, the yield of the product 15 was slightly lower (88%).
The products in the form of dihydrobromide salts (Schemes 2-4) precipitated from the reaction mixture and can be easy isolated by filtration.It should be emphasized that these products did not require additional purification.The compounds obtained were generally white, beige, yellowish or slightly orange-tinted powders.
Compounds, containing vinyloxy groups, are valuable intermediates for organic synthesis, capable of electrophilic addition and polymerization.The amine functional- The main part of the primary amines gave the products 9-14 in 91-96% yields.In the case of tert-butylamine, the yield of the product 15 was slightly lower (88%).
The products in the form of dihydrobromide salts (Schemes 2-4) precipitated from the reaction mixture and can be easy isolated by filtration.It should be emphasized that these products did not require additional purification.The compounds obtained were generally white, beige, yellowish or slightly orange-tinted powders.
Compounds, containing vinyloxy groups, are valuable intermediates for organic synthesis, capable of electrophilic addition and polymerization.The amine functionalized with the vinyloxy group 2-vinyloxyethylamine reacted with compound 2 to form the product 16 in 94% yield (Scheme 5).
ized with the vinyloxy group 2-vinyloxyethylamine reacted with compound 2 to form the product 16 in 94% yield (Scheme 5).2-Vinyloxyethylamine was obtained by the vinylation of 2-hydroxyethylamine with acetylene in the presence of an alkali.

Se
A very convenient and effective method for obtaining corresponding diamino derivatives as free bases was developed.Performing the reaction in acetonitrile in the presence of sodium or potassium carbonate ensures the selective formation of the corresponding diamino products due to the selective neutralization of hydrobromide with these basic reagents.Sodium or potassium carbonate was added at the beginning of the process after the amine was added to the reaction mixture.It should be noted that the possible formation of unsaturated products by the dehydrobromination reaction with the carbonates was not observed.
We suppose that the products 16 and 17, containing two vinyloxy groups, can be useful monomers in oligomerization or polymerization reactions to produce new materials, containing a 9-selenabicyclo[3.3.1]nonanescaffold and ammonium or amino groups.These very interesting products can be also involved in further functionalization reactions of vinyloxy or amino groups.
It was found that, to obtain the corresponding diamine derivatives with high yields, it is necessary to use sodium or potassium carbonate in a 1.5-2-fold excess compared to stoichiometric quantities.
This method has proved to be very effective in the case of both primary and secondary amines.The reaction of isopropylamine, allylamine, butylamine, isobutylamine, tert-butylamine, benzylamine and phenylamine with compound 2 was carried out in the Na2CO3/acetonitrile system at room temperature, affording corresponding 2,6-diamino derivatives 18-24 in 90-96% yields (Scheme 6).Scheme 6.The synthesis of the products 18-24 from primary amines and compound 2.
Secondary amines such as diethylamine, diisopropylamine and diallylamine were efficiently involved in the reaction with compound 2 in acetonitrile at room temperature Scheme 5.The synthesis of compounds 16 and 17.

2-Vinyloxyethylamine was obtained by the vinylation of 2-hydroxyethylamine with acetylene in the presence of an alkali.
A very convenient and effective method for obtaining corresponding diamino derivatives as free bases was developed.Performing the reaction in acetonitrile in the presence of sodium or potassium carbonate ensures the selective formation of the corresponding diamino products due to the selective neutralization of hydrobromide with these basic reagents.Sodium or potassium carbonate was added at the beginning of the process after the amine was added to the reaction mixture.It should be noted that the possible formation of unsaturated products by the dehydrobromination reaction with the carbonates was not observed.
We suppose that the products 16 and 17, containing two vinyloxy groups, can be useful monomers in oligomerization or polymerization reactions to produce new materials, containing a 9-selenabicyclo[3.3.1]nonanescaffold and ammonium or amino groups.These very interesting products can be also involved in further functionalization reactions of vinyloxy or amino groups.
It was found that, to obtain the corresponding diamine derivatives with high yields, it is necessary to use sodium or potassium carbonate in a 1.5-2-fold excess compared to stoichiometric quantities.
This method has proved to be very effective in the case of both primary and secondary amines.The reaction of isopropylamine, allylamine, butylamine, isobutylamine, tertbutylamine, benzylamine and phenylamine with compound 2 was carried out in the Na 2 CO 3 /acetonitrile system at room temperature, affording corresponding 2,6-diamino derivatives 18-24 in 90-96% yields (Scheme 6).2-Vinyloxyethylamine was obtained by the vinylation of 2-hydroxyethylamine w acetylene in the presence of an alkali.

Se
A very convenient and effective method for obtaining corresponding diamino rivatives as free bases was developed.Performing the reaction in acetonitrile in presence of sodium or potassium carbonate ensures the selective formation of the cor sponding diamino products due to the selective neutralization of hydrobromide w these basic reagents.Sodium or potassium carbonate was added at the beginning of process after the amine was added to the reaction mixture.It should be noted that possible formation of unsaturated products by the dehydrobromination reaction with carbonates was not observed.
We suppose that the products 16 and 17, containing two vinyloxy groups, can useful monomers in oligomerization or polymerization reactions to produce new ma rials, containing a 9-selenabicyclo[3.3.1]nonanescaffold and ammonium or am groups.These very interesting products can be also involved in further functionalizat reactions of vinyloxy or amino groups.
It was found that, to obtain the corresponding diamine derivatives with high yie it is necessary to use sodium or potassium carbonate in a 1.5-2-fold excess compared stoichiometric quantities.
This method has proved to be very effective in the case of both primary and s ondary amines.The reaction of isopropylamine, allylamine, butylamine, isobutylami tert-butylamine, benzylamine and phenylamine with compound 2 was carried out in Na2CO3/acetonitrile system at room temperature, affording corresponding 2,6-diam derivatives 18-24 in 90-96% yields (Scheme 6).Scheme 6.The synthesis of the products 18-24 from primary amines and compound 2.
Secondary amines such as diethylamine, diisopropylamine and diallylamine w efficiently involved in the reaction with compound 2 in acetonitrile at room temperat Scheme 6.The synthesis of the products 18-24 from primary amines and compound 2.
Secondary amines such as diethylamine, diisopropylamine and diallylamine were efficiently involved in the reaction with compound 2 in acetonitrile at room temperature in the presence of sodium carbonate to form corresponding 2,6-diamino derivatives 25-27 in 93-97% yields (Scheme 7).
in the presence of sodium carbonate to form corresponding 2,6-diamino derivatives 25-27 in 93-97% yields (Scheme 7).When the reaction of morpholine, piperidine and pyrrolidine with compound 2 was carried out in acetonitrile at room temperature in the presence of sodium or potassium carbonate, corresponding 2,6-diamino derivatives 28-30 were obtained in 91-95% yields (Scheme 8).We succeeded in the preparation of product 31, containing two unsubstituted amino groups, by reacting compound 2 with ammonia in a two-phase system: methylene chloride-10% aqueous ammonia solution containing potassium carbonate.The reaction mixture was allowed to stir for 40 h at room temperature.Despite these very simple conditions, the target product 31 was obtained in 81% yield (Scheme 9).A higher yield of product 31 was achieved starting from diazido derivative 32, which was obtained from compound 2 and sodium azide in aqueous acetonitrile.The When the reaction of morpholine, piperidine and pyrrolidine with compound 2 was carried out in acetonitrile at room temperature in the presence of sodium or potassium carbonate, corresponding 2,6-diamino derivatives 28-30 were obtained in 91-95% yields (Scheme 8).When the reaction of morpholine, piperidine and pyrrolidine with compound 2 was carried out in acetonitrile at room temperature in the presence of sodium or potassium carbonate, corresponding 2,6-diamino derivatives 28-30 were obtained in 91-95% yields (Scheme 8).We succeeded in the preparation of product 31, containing two unsubstituted amino groups, by reacting compound 2 with ammonia in a two-phase system: methylene chloride-10% aqueous ammonia solution containing potassium carbonate.The reaction mixture was allowed to stir for 40 h at room temperature.Despite these very simple conditions, the target product 31 was obtained in 81% yield (Scheme 9).A higher yield of product 31 was achieved starting from diazido derivative 32, which was obtained from compound 2 and sodium azide in aqueous acetonitrile.The Scheme 8.The synthesis of compounds 28-30.
We succeeded in the preparation of product 31, containing two unsubstituted amino groups, by reacting compound 2 with ammonia in a two-phase system: methylene chloride-10% aqueous ammonia solution containing potassium carbonate.The reaction mixture was allowed to stir for 40 h at room temperature.Despite these very simple conditions, the target product 31 was obtained in 81% yield (Scheme 9).When the reaction of morpholine, piperidine and pyrrolidine with compound 2 was carried out in acetonitrile at room temperature in the presence of sodium or potassium carbonate, corresponding 2,6-diamino derivatives 28-30 were obtained in 91-95% yields (Scheme 8).We succeeded in the preparation of product 31, containing two unsubstituted amino groups, by reacting compound 2 with ammonia in a two-phase system: methylene chloride-10% aqueous ammonia solution containing potassium carbonate.The reaction mixture was allowed to stir for 40 h at room temperature.Despite these very simple conditions, the target product 31 was obtained in 81% yield (Scheme 9).A higher yield of product 31 was achieved starting from diazido derivative 32, which was obtained from compound 2 and sodium azide in aqueous acetonitrile.The Scheme 9. Two methods for the preparation of compound 31.
A higher yield of product 31 was achieved starting from diazido derivative 32, which was obtained from compound 2 and sodium azide in aqueous acetonitrile.The reduction of diazido derivative 32 with triphenylphosphine in THF followed by the hydrolysis afforded the target product 31 in 90% yield (Scheme 9).
It should be emphasized that the developed methods demonstrate the valuable features of click chemistry: high yields of target products, simple reaction conditions (room temperature), accessible starting materials, broad-scope reactions (ammonia, both primary and secondary amines with various substituents: Et, Bu, i-Bu, i-Pr, t-Bu, Bn, Ph, morpholine, piperidine, pyrrolidine and 2-vinyloxyethylamine) and convenient isolation procedures (no additional purification of the products required).
It is worth noting that the adducts of selenium dibromide with simple alkenes 33-35 do not undergo nucleophilic substitution with amines.We found that the reactions of diethyl, diisopropyl and triethylamine with the SeBr 2 -alkene adducts 33-35 led to the formation of parent alkenes (Scheme 10).We assume that under the action of the amines, a process occurs that is the reverse reaction of the addition of selenium dibromide to alkenes.However, the use of compound 2 made it possible to carry out the nucleophilic substitution reactions with amines.
reduction of diazido derivative 32 with triphenylphosphine in THF followed by the hydrolysis afforded the target product 31 in 90% yield (Scheme 9).
It should be emphasized that the developed methods demonstrate the valuable features of click chemistry: high yields of target products, simple reaction conditions (room temperature), accessible starting materials, broad-scope reactions (ammonia, both primary and secondary amines with various substituents: Et, Bu, i-Bu, i-Pr, t-Bu, Bn, Ph, morpholine, piperidine, pyrrolidine and 2-vinyloxyethylamine) and convenient isolation procedures (no additional purification of the products required).
It is worth noting that the adducts of selenium dibromide with simple alkenes 33-35 do not undergo nucleophilic substitution with amines.We found that the reactions of diethyl, diisopropyl and triethylamine with the SeBr2-alkene adducts 33-35 led to the formation of parent alkenes (Scheme 10).We assume that under the action of the amines, a process occurs that is the reverse reaction of the addition of selenium dibromide to alkenes.However, the use of compound 2 made it possible to carry out the nucleophilic substitution reactions with amines.
Scheme 10.The reactions of the SeBr2-alkene adducts with amines.
The reaction of dibromo compound 2 with triethylamine, which is more basic than other amines, proceeded non-selectively and was accompanied by dehydrobromination with the formation of a mixture of products.We found that the dehydrobromination of product 2 can be carried out more selectively by heating this compound in acetonitrile, which plays the role of a soft dehydrobromination reagent in this case.Heating compound 2 in acetonitrile made it possible to eliminate selectively one hydrobromide molecule from one molecule of compound 2 with the formation of the CH=CH moiety and to obtain a very interesting product, containing one double bond and one bromine atom: 6-bromo-9-selenabicyclo[3.3.1]nonene-2(36).
Refluxing compound 2 in acetonitrile (~82 °C) for 3 h gave nonene 36 in about 50% yield, but the selectivity of this reaction was low and it was difficult to purify the target product.It was found that it is preferable to carry out the heating reaction at a lower temperature (55-65 °C) with an increase in the reaction time to 12 h.Under these conditions, the target product 36 was selectively obtained in 90% yield and could be easily purified (Scheme 11).The reaction of dibromo compound 2 with triethylamine, which is more basic than other amines, proceeded non-selectively and was accompanied by dehydrobromination with the formation of a mixture of products.We found that the dehydrobromination of product 2 can be carried out more selectively by heating this compound in acetonitrile, which plays the role of a soft dehydrobromination reagent in this case.Heating compound 2 in acetonitrile made it possible to eliminate selectively one hydrobromide molecule from one molecule of compound 2 with the formation of the CH=CH moiety and to obtain a very interesting product, containing one double bond and one bromine atom: 6-bromo-9selenabicyclo[3.3.1]nonene-2(36).
Refluxing compound 2 in acetonitrile (~82 • C) for 3 h gave nonene 36 in about 50% yield, but the selectivity of this reaction was low and it was difficult to purify the target product.It was found that it is preferable to carry out the heating reaction at a lower temperature (55-65 • C) with an increase in the reaction time to 12 h.Under these conditions, the target product 36 was selectively obtained in 90% yield and could be easily purified (Scheme 11).
Int. J. Mol.Sci.2023, 24, x FOR PEER REVIEW 8 of 23 reduction of diazido derivative 32 with triphenylphosphine in THF followed by the hydrolysis afforded the target product 31 in 90% yield (Scheme 9).It should be emphasized that the developed methods demonstrate the valuable features of click chemistry: high yields of target products, simple reaction conditions (room temperature), accessible starting materials, broad-scope reactions (ammonia, both primary and secondary amines with various substituents: Et, Bu, i-Bu, i-Pr, t-Bu, Bn, Ph, morpholine, piperidine, pyrrolidine and 2-vinyloxyethylamine) and convenient isolation procedures (no additional purification of the products required).
It is worth noting that the adducts of selenium dibromide with simple alkenes 33-35 do not undergo nucleophilic substitution with amines.We found that the reactions of diethyl, diisopropyl and triethylamine with the SeBr2-alkene adducts 33-35 led to the formation of parent alkenes (Scheme 10).We assume that under the action of the amines, a process occurs that is the reverse reaction of the addition of selenium dibromide to alkenes.However, the use of compound 2 made it possible to carry out the nucleophilic substitution reactions with amines.The reaction of dibromo compound 2 with triethylamine, which is more basic than other amines, proceeded non-selectively and was accompanied by dehydrobromination with the formation of a mixture of products.We found that the dehydrobromination of product 2 can be carried out more selectively by heating this compound in acetonitrile, which plays the role of a soft dehydrobromination reagent in this case.Heating compound 2 in acetonitrile made it possible to eliminate selectively one hydrobromide molecule from one molecule of compound 2 with the formation of the CH=CH moiety and to obtain a very interesting product, containing one double bond and one bromine atom: 6-bromo-9-selenabicyclo[3.3.1]nonene-2(36).
Refluxing compound 2 in acetonitrile (~82 °C) for 3 h gave nonene 36 in about 50% yield, but the selectivity of this reaction was low and it was difficult to purify the target product.It was found that it is preferable to carry out the heating reaction at a lower temperature (55-65 °C) with an increase in the reaction time to 12 h.Under these conditions, the target product 36 was selectively obtained in 90% yield and could be easily purified (Scheme 11).This remarkable reaction makes it possible to develop the convenient synthesis of 6-bromo-9-selenabicyclo[3.3.1]nonene-2(36), which serves as a promising starting material in further transformations and the preparation of a number of selenabicyclo[3.3.1]nonenederivatives.
The reactions of monobromide 36 with alkylamines and ammonia, under the same condition as in the previous reactions with compound 2, gave mixtures of products.However, we succeeded in the preparation of 6-azido-9-selenabicyclo[3.3.1]nonene-237 and corresponding amino derivative 38.Monobromide 36 was converted to azide 37 via the reaction with sodium azide in aqueous acetonitrile and then the obtained azide was reduced with triphenylphosphine in THF followed by a hydrolysis (Scheme 12).As a result, 6-amino-9-selenabicyclo[3.3.1]nonene-2(38) was obtained in 88% yield.
The reactions of monobromide 36 with alkylamines and ammonia, under the same condition as in the previous reactions with compound 2, gave mixtures of products.However, we succeeded in the preparation of 6-azido-9-selenabicyclo[3.3.1]nonene-237 and corresponding amino derivative 38.Monobromide 36 was converted to azide 37 via the reaction with sodium azide in aqueous acetonitrile and then the obtained azide was reduced with triphenylphosphine in THF followed by a hydrolysis (Scheme 12).As a result, 6-amino-9-selenabicyclo[3.3.1]nonene-2(38) was obtained in 88% yield.A very convenient and selective synthesis of alkoxy derivatives of selenabicyclo[3.3.1]nonene39-42 in 94-99% yield was developed by nucleophilic substitutions of bromine in compound 36 by alcohols.We found that the alkoxylation reaction proceeded efficiently in acetonitrile in the presence of weakly basic sodium bicarbonate at room temperature (Scheme 13).Filtration followed by the solvent removal resulted in the pure target products 39-42, which did not require additional purification.This reaction also meets the criteria of click chemistry.
The resulting 9-selenabicyclo[3.3.1]nonene-2derivatives represent a new, very promising class of organoselenium heterocyclic compounds.The presence of the double bond and very active bromine atom opens new possibilities for functionalization.We plan to develop the chemistry of this new class of compounds using bromo derivative 36 as a starting material, as well as other approaches.
The high reactivity of compounds 2 and 36 is determined by the strong anchimeric assistance effect of the selenium atom [56].It is assumed that the nucleophilic substitution of the bromine atom in compounds 2 and 36 proceeds via the formation of corresponding seleniranium intermediates [56].We suppose that the dehydrobromination of compound 2 (Scheme 11) occurs as an anti-process, which is facilitated by acetonitrile as a polar solvent.Acetonitrile also exhibits the properties of a weak base in this reaction.The selenium atom is in an anti-position relative to the bromine atom and the anti-elimination of hydrobromide in the Br-CH-CH-Se group does not occur.However, there is a hydro-Scheme 12.The synthesis of 6-amino-9-selenabicyclo[3.3.1]nonene-2(38).
A very convenient and selective synthesis of alkoxy derivatives of selenabicyclo[3.3.1]nonene 39-42 in 94-99% yield was developed by nucleophilic substitutions of bromine in compound 36 by alcohols.We found that the alkoxylation reaction proceeded efficiently in acetonitrile in the presence of weakly basic sodium bicarbonate at room temperature (Scheme 13).
rial in further transformations and the preparation of a number of selenabicyclo[3.3.1]nonenederivatives.
The reactions of monobromide 36 with alkylamines and ammonia, under the same condition as in the previous reactions with compound 2, gave mixtures of products.However, we succeeded in the preparation of 6-azido-9-selenabicyclo[3.3.1]nonene-237 and corresponding amino derivative 38.Monobromide 36 was converted to azide 37 via the reaction with sodium azide in aqueous acetonitrile and then the obtained azide was reduced with triphenylphosphine in THF followed by a hydrolysis (Scheme 12).As a result, 6-amino-9-selenabicyclo[3.3.1]nonene-2(38) was obtained in 88% yield.A very convenient and selective synthesis of alkoxy derivatives of selenabicyclo[3.3.1]nonene39-42 in 94-99% yield was developed by nucleophilic substitutions of bromine in compound 36 by alcohols.We found that the alkoxylation reaction proceeded efficiently in acetonitrile in the presence of weakly basic sodium bicarbonate at room temperature (Scheme 13).Filtration followed by the solvent removal resulted in the pure target products 39-42, which did not require additional purification.This reaction also meets the criteria of click chemistry.
The resulting 9-selenabicyclo[3.3.1]nonene-2derivatives represent a new, very promising class of organoselenium heterocyclic compounds.The presence of the double bond and very active bromine atom opens new possibilities for functionalization.We plan to develop the chemistry of this new class of compounds using bromo derivative 36 as a starting material, as well as other approaches.
The high reactivity of compounds 2 and 36 is determined by the strong anchimeric assistance effect of the selenium atom [56].It is assumed that the nucleophilic substitution of the bromine atom in compounds 2 and 36 proceeds via the formation of corresponding seleniranium intermediates [56].We suppose that the dehydrobromination of compound 2 (Scheme 11) occurs as an anti-process, which is facilitated by acetonitrile as a polar solvent.Acetonitrile also exhibits the properties of a weak base in this reaction.The selenium atom is in an anti-position relative to the bromine atom and the anti-elimination of hydrobromide in the Br-CH-CH-Se group does not occur.However, there is a hydro-Scheme 13.The synthesis of 6-alkoxy-9-selenabicyclo[3.3.1]nonenes-239-42.
Filtration followed by the solvent removal resulted in the pure target products 39-42, which did not require additional purification.This reaction also meets the criteria of click chemistry.
The resulting 9-selenabicyclo[3.3.1]nonene-2derivatives represent a new, very promising class of organoselenium heterocyclic compounds.The presence of the double bond and very active bromine atom opens new possibilities for functionalization.We plan to develop the chemistry of this new class of compounds using bromo derivative 36 as a starting material, as well as other approaches.
The high reactivity of compounds 2 and 36 is determined by the strong anchimeric assistance effect of the selenium atom [56].It is assumed that the nucleophilic substitution of the bromine atom in compounds 2 and 36 proceeds via the formation of corresponding seleniranium intermediates [56].We suppose that the dehydrobromination of compound 2 (Scheme 11) occurs as an anti-process, which is facilitated by acetonitrile as a polar solvent.Acetonitrile also exhibits the properties of a weak base in this reaction.The selenium atom is in an anti-position relative to the bromine atom and the anti-elimination of hydrobromide in the Br-CH-CH-Se group does not occur.However, there is a hydrogen atom in an antiposition to the bromine atom in the Br-CH-CH 2 -fragment and the elimination proceeds selectively in this fragment.
Acetonitrile was found to be a solvent of choice for these nucleophilic reactions (Schemes 2-8 and 11-13).Like DMSO and DMF, acetonitrile is an aprotic bipolar solvent, which considerably facilitated nucleophilic substitutions.However, unlike DMSO and DMF, acetonitrile has a lower boiling point (~82 • C) and can be easily removed from the reaction mixture.The products can be purified from acetonitrile in a vacuum, but doing the same using DMSO or DMF as a solvent is very difficult.
The selenium atom is sterically accessible in the rigid configuration of the 9-selenabicy clo[3.3.1]nonaneframework and its derivatives are very promising compounds for the manifestation of GPx mimetic activity.The obtained water-soluble dihydrobromide products were investigated as GPx mimics.The oxidation of dithiothreitol with tert-butyl hydroperoxide in deuterated water was used as the model reaction [65][66][67][68][69][70].The synthesized products played the role of catalysts (10% mol).The progress of the redox reaction was monitored by 1 H NMR spectroscopy at room temperature after mixing the reagents and a tested product (tert-butyl hydroperoxide, dithiothreitol, 0.025 mmol; a tested product, 0.0025 mmol; D 2 O, 0.5 mL).The results obtained for most active products are presented in Figure 3.
which considerably facilitated nucleophilic substitutions.However, unlike DMSO and DMF, acetonitrile has a lower boiling point (~82 °C) and can be easily removed from the reaction mixture.The products can be purified from acetonitrile in a vacuum, but doing the same using DMSO or DMF as a solvent is very difficult.
The selenium atom is sterically accessible in the rigid configuration of the 9-selenabicyclo[3.3.1]nonaneframework and its derivatives are very promising compounds for the manifestation of GPx mimetic activity.The obtained water-soluble dihydrobromide products were investigated as GPx mimics.The oxidation of dithiothreitol with tert-butyl hydroperoxide in deuterated water was used as the model reaction [65][66][67][68][69][70].The synthesized products played the role of catalysts (10% mol).The progress of the redox reaction was monitored by 1 H NMR spectroscopy at room temperature after mixing the reagents and a tested product (tert-butyl hydroperoxide, dithiothreitol, 0.025 mmol; a tested product, 0.0025 mmol; D2O, 0.5 mL).The results obtained for most active products are presented in Figure 3.The catalytic activities of the dihydrobromide products were estimated by the measurement of half-lives (T1/2), representing the time required to oxidize half of the dithiotreitol to its disulfide (this is a generally accepted methodology [65][66][67][68][69][70]). It was found that compounds 4 and 10, containing diethylamino and isopropylamino groups, showed the greatest activity of approximately the same value among the tested compounds (Figure 3).The activity of the products 6 and 14 with pyrrolidine and phenylamino substituents were also very high and about the same value.The half-lives (T1/2) of these four products were in the range of 30-35 min.The comparison of the activity of these products, 4, 6, 10 and 14, with known data [65][66][67][68][69][70] allows us to consider them compounds with high activity.Less active were compounds 9 and 12, containing allylamino (T1/2 = 61 min) and isobutylamino (T1/2 = 86 min) groups.The other products showed T1/2 > 100 min.
The amino groups can exhibit electronic and steric effects, influencing the main catalytic center-the selenium atom in compounds 4-16.We assume that the obtained results show the importance of the steric factor for this family of compounds.Diethylamino and isopropylamino substituents show low steric hindrance at the selenium atom, which can participate in the catalytic cycle.This is also true for the pyrrolidine and phenylamino The catalytic activities of the dihydrobromide products were estimated by the measurement of half-lives (T 1/2 ), representing the time required to oxidize half of the dithiotreitol to its disulfide (this is a generally accepted methodology [65][66][67][68][69][70]). It was found that compounds 4 and 10, containing diethylamino and isopropylamino groups, showed the greatest activity of approximately the same value among the tested compounds (Figure 3).The activity of the products 6 and 14 with pyrrolidine and phenylamino substituents were also very high and about the same value.The half-lives (T 1/2 ) of these four products were in the range of 30-35 min.The comparison of the activity of these products, 4, 6, 10 and 14, with known data [65][66][67][68][69][70] allows us to consider them compounds with high activity.Less active were compounds 9 and 12, containing allylamino (T 1/2 = 61 min) and isobutylamino (T 1/2 = 86 min) groups.The other products showed T 1/2 > 100 min.
The amino groups can exhibit electronic and steric effects, influencing the main catalytic center-the selenium atom in compounds 4-16.We assume that the obtained results show the importance of the steric factor for this family of compounds.Diethylamino and isopropylamino substituents show low steric hindrance at the selenium atom, which can participate in the catalytic cycle.This is also true for the pyrrolidine and phenylamino substituents, which exhibit lower steric effects compared to that of the piperidine and morpholine groups.It is worth noting that the phenylamino group has a flat configuration.
We suppose that the catalytic cycle [65][66][67][68][69][70] includes the formation of intermediate selenoxides, which are formed by the oxidation of the products with tert-butyl hydroperoxide.The selenoxides are very reactive intermediates, which oxidase dithiotreitol to its cyclic disulfide with the formation of water and the regeneration of the catalysts [67].This process is energetically very favorable.
The structural assignments of the synthesized compounds were made using 1 H, 13 C and 77 Se NMR spectroscopy including two-dimensional experiments and were confirmed by elemental analysis.The structures of selenabicyclo[3.3.1]nonene-2derivatives were proved by NMR spectroscopy including COSY, HMBC and HSQC experiments.
When heated in a vacuum (1 mm Hg), the obtained compounds decompose at temperatures above 100-110 • C and it is hardly possible to measure their boiling point.

General Information
The 1 H (400.1 MHz), 13 C (100.6 MHz) and 77 Se (76 MHz) NMR spectra were recorded on a Bruker DPX-400 spectrometer (Bruker BioSpin GmbH, Rheinstetten, Germany) in CDCl 3 (referred to the residual solvent peaks of CDCl 3 , δ = 7.27 and 77.16 ppm for 1 H and 13 C NMR, respectively) peaks, δ = 7.27 and 77.16 ppm for 1 H and 13 C NMR, respectively), DMSO-d 6 (referred to the residual solvent peaks of DMSO-d 6 , δ = 2.50 and 39.50 ppm for 1 H and 13 C NMR, respectively), and D 2 O (referred to the external standard, hexamethyldisiloxane, δ = 0.055 and 1.97 ppm for 1 H and 13 C NMR, respectively).The 77 Se NMR spectra were referred to dimethyl selenide as standard.The NMR spectra can be found in Supplementary Materials.IR spectra were recorded on a Vertex 70 spectrometer (Bruker BioSpin GmbH, Rheinstetten, Germany).Elemental analysis was performed on a Thermo Scientific Flash 2000 Elemental Analyzer (Thermo Fisher Scientific Inc., Milan, Italy).Melting points were determined on a Kofler Hot-Stage Microscope PolyTherm A apparatus (Wagner & Munz GmbH, München, Germany).The distilled organic solvents and degassed water were used in syntheses.
3.2.The Synthesis of Dihydrobromide Salts 4-8 from Secondary Amines 2,6-Bis(diethylamino)-9-selenabicyclo[3.3.1]nonanedihydrobromide (4).A solution of diethylamine (0.15 g, 2.05 mmol) in methylene chloride (1 mL) was added dropwise to a solution of compound 2 (0.3 g, 0.86 mmol) in methylene chloride (4 mL) with stirring at room temperature.The reaction mixture was stirred overnight (16 h) at room temperature.Cold hexane (5 mL) was added to the mixture.The formed precipitate was filtered off, washed with cold hexane and dried in a vacuum giving the product (382 mg, 90% yield) as a white powder, mp 184-185  (5).A solution of diallylamine (0.2 g, 2.06 mmol) in acetonitrile (1 mL) was added dropwise to a mixture of compound 2 (0.3 g, 0.86 mmol) and acetonitrile (4 mL) with stirring at room temperature.The reaction mixture was stirred overnight (16 h) at room temperature.Cold hexane (5 mL) was added to the mixture.The formed precipitate was filtered off, washed with cold acetonitrile and dried in a vacuum, giving the product (435 mg, 93% yield) mp 161-162 • C as a white powder. 1   (9).A solution of allylamine (0.117 g, 2.05 mmol) in acetonitrile (1 mL) was added dropwise to a mixture of compound 2 (0.347 g, 1 mmol) and acetonitrile (9 mL) with stirring at room temperature.The reaction mixture was stirred overnight (20 h) at room temperature.Cold hexane (5 mL) was added to the mixture.The formed precipitate was filtered off, washed with cold acetonitrile and dried in a vacuum, giving the product (437 mg, 95% yield) mp 230-231 • C as a white powder. 1   (25).A solution of diethylamine (0.131 g, 1.8 mmol) in acetonitrile (1 mL) was added dropwise to a mixture of compound 2 (0.3 g, 0.86 mmol) and acetonitrile (9 mL) followed by the addition of powdered Na 2 CO 3 (0.28 g, 3.26 mmol) with stirring at room temperature.The reaction mixture was stirred overnight (20 h) at room temperature.The main part of the solvent was removed on a rotary evaporator and water (10 mL) and methylene chloride (15 mL) were added.The aqueous phase was extracted with methylene chloride (3 × 15 mL).The organic phase was dried over Na 2 SO 4 and the solvent was removed on a rotary evaporator.The residue was dried in a vacuum, giving the product (278 mg, 97% yield) as a grey oil. 13 The Synthesis of diamine 31 from compound 2. A solution of compound 2 (0.347 g, 1 mmol) in methylene chloride (10 mL) was added to a 10% solution of ammonia (15 mL) containing K 2 CO 3 (1 g).The reaction mixture was stirred for 48 h at room temperature.The organic phase was separated, dried over Na 2 SO 4 , and the solvent was removed on a rotary evaporator.The residue was subjected to column chromatography (eluent: hexane, then hexane/chloroform 8:1, then hexane/chloroform 4:1), giving the product (178 mg, 81% yield).(36).A solution of compound 2 (0.694 g, 2 mmol) in acetonitrile (10 mL) was heated at 55-65 • C with stirring for 12 h.Acetonitrile was removed on a rotary evaporator.The residue was analyzed by NMR, which showed an 80% conversion of compound 2, and subjected to column chromatography (eluent: hexane, then hexane/chloroform 8:1), giving the product (383 mg, 90% yield based on consumed compound 2). 1   37).A solution of sodium azide (1 g, 15.4 mmol) in water (5.3 mL) was added dropwise to a mixture of compound 36 (0.532 g, 2 mmol) and acetonitrile (8 mL) with stirring at room temperature.The reaction mixture was stirred overnight (16 h) at room temperature.Acetonitrile was removed on a rotary evaporator and the residue was extracted with methylene chloride (3 × 10 mL).The organic phase was dried over CaCl 2 , the solvent was removed on a rotary evaporator and the residue was dried in a vacuum, giving the product (433 mg, 95% yield) as a grey oil.(39).Methanol (0.4 mL) and NaHCO 3 (0.05 g) were added to a solution of bromide 36 (133 mg, 0.5 mmol) in acetonitrile (2 mL).The mixture was stirred overnight (20 h) at room temperature and filtered.The solvent was on a rotary evaporator and the residue was dried in a vacuum to give the product as a colorless oil (yield: 107 mg, 99%), which did not require additional purification. 1

Conclusions
The efficient and selective synthesis of 6-bromo-9-selenabicyclo[3. The methods of amination of 2,6-dibromo-9-selenabicyclo[3.3.1]nonane are characterized by high yields of target products (88-98%), high selectivity and simple reaction conditions (room temperature), broad-scope reactions (ammonia, both primary and secondary amines with various substituents (Et, i-Pr, Bu, i-Bu, t-Bu, PhCH 2, Ph, morpholine, piperidine, pyrrolidine and 2-vinyloxyethylamine) and convenient isolation procedures.The products were isolated from the reaction mixture by filtration (dihydrobromide salts) or by solvent removing (free base diamino derivatives) and did not require additional purifications.These methods meet the criteria of click chemistry.

Scheme 3 .
Scheme 3. The synthesis of the products 6-8 from cyclic amines and compound 2.

Scheme 3 .
Scheme 3. The synthesis of the products 6-8 from cyclic amines and compound 2.

Scheme 9 .
Scheme 9. Two methods for the preparation of compound 31.

Scheme 9 .
Scheme 9. Two methods for the preparation of compound 31.

Scheme 9 .
Scheme 9. Two methods for the preparation of compound 31.